Wild-type p53-induced phosphatase 1 (Wip1) is a Mg2+-dependent serine/threonine protein phosphatase that is expressed in response to ionizing or ultra-violet (UV) radiation in a manner that is dependent on the tumor suppressor gene product p53. Its role in cancer was first suggested by Fiscella et al., Proceedings of the National Academy of Sciences, U.S.A. 94: 6048-6053 (1997), which reported Wip1 as an important inhibitor of growth, since ectopic expression of WIP1 (also known as PPMD1) in a human glioblastoma cell line (T98G) resulted in fewer colonies of cells. In contrast to these results, Wip1 was shown by Takekawa et al., EMBO Journal 19(23): 6517-6526 (2000), to dephosphorylate the kinase p38, which functions to activate p53 for the induction of apoptosis and transcription in response to environmental stress, thereby rendering Wip1 anti-apoptotic as opposed to anti-proliferative.
Consistent with Takekawa et al., Wip1 has been shown by the present inventors to be a positive regulator of tumorigenesis. WIP1, located at chromosome 17q22/q23 by FISH analysis, was found amplified in human breast tumor cell lines as well as in approximately 11% of primary breast tumors as determined by Northern blot analysis, Southern blot analysis, and tissue microarray analysis. Furthermore, exogeneous expression of WIP1 in cells expressing H-Ras-V12 resulted in a decrease in p53-mediated apoptosis and a partial rescue of these cells from cell cycle arrest. Moreover, Wip1 was demonstrated as a negative regulator of p38, since UV-induced activation of p38 kinase was significantly attenuated in breast cell lines in which the Wip1 gene was amplified and overexpressed (BT-474 and MCF7) compared to a breast line (MDA-MB436) without Wip1 amplification. Taken together, these results indicate that WIP1 is a candidate proto-oncogene involved in tumorigenesis and, thus, represents an attractive new target for cancer therapy.
In view of the foregoing, the present invention provides materials and methods for treating cancer in a mammal that expresses elevated levels of Wip1. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.